The goal of this project is to understand genetically controlled mechanisms involved in host defense against retrovirus-induced disease. In this work we have been studying both spontaneous recovery and generation of protective immunity using Friend virus complex (FV)-induced erythroleukemia in mice as a model for human retroviral diseases including AIDS and certain leukemias. Previous experiments indicated that both susceptibility virus- induced immunosuppression and lack of ability to spontaneously recover from leukemia were influenced by the H-2D subregion. More recent data now shows that the predominant genetic influence on generation of protective immunity is mediated by the H-2l subregion. This was specifically documented in mice immunized by inoculation with live recombinant vaccinia virus expressing the FV envelope gene. Our latest experiments indicate that the H-2l region regulates ability to prime T lymphocytes with FV envelope antigens. The H-2l gene influences this immunological priming by controlling the ability of macrophages and other cells to present FV envelop antigens correctly to the specific T lymphocytes. This mechanism was directly demonstrated in vitro and antigen presentation could be inhibited only by appropriate anti-H-2l monoclonal antibodies. Similar genetic regulatory influences are likely to exist in humans and may affect potency of vaccines being developed against human retroviruses.